Vagal stimulation for improving cardiac function in heart failure or CHF patients

ABSTRACT

Exemplary methods for decreasing workload, maintaining or increasing cardiac output and/or achieving a desirable autonomic balance by stimulating one or more parasympathetic nerves. Various exemplary methods include delivering one or more stimulation pulses postinspiration and/or based at least in part on detection of one or more cardiac event. Other methods and/or devices are also disclosed.

PRIORITY CLAIM AND CROSS-REFERENCE TO RELATED APPLICATIONS

The instant application claims priority to U.S. ProvisionalApplications: 1) Ser. No. 60/388,709, filed Jun. 12, 2002, entitled“Parasympathetic Nerve Stimulation for CHF Patients,” to Shelchuk; 2)Ser. No. 60/389,053, filed Jun. 12, 2002; 3) 60/388,784, filed Jun. 12,2002; 4) Ser. No. 60/388,623, filed Jun. 12, 2002; 5) 60/388,707, filedJun. 12, 2002; and 6) nonprovisional U.S. application Ser. No.10/420,998, filed Apr. 21, 2003, entitled “Parasympathetic NerveStimulation for ICD and/or ATP Patients,” to Sheichuk; all aboveapplications are incorporated by reference herein.

The instant application is related to co-pending U.S. patent applicationhaving Ser. No. 10/460,149, filed Jun. 11, 2003, filed concurrentlyherewith, entitled “Parasympathetic Nerve Stimulation for Termination ofSupraventricular Arrhythmias,” to Shelchuk, which is incorporated byreference herein and which claims priority to a U.S. ProvisionalApplication having Ser. No. 60/388,784, filed Jun. 12, 2002, which isalso incorporated by reference herein.

The instant application is related to co-pending U.S. patent applicationhaving Ser. No. 10/460,145, filed Jun. 11, 2003, filed concurrentlyherewith, entitled “Parasympathetic Nerve Stimulation for Control of AVConduction”, to Shelchuk; Bornzin and Falkenberg, which is incorporatedby reference herein and which claims priority to a U.S. ProvisionalApplication having Ser. No. 60/389,053, filed Jun. 12, 2002, which isalso incorporated by reference herein.

The instant application is related to co-pending U.S. patent applicationhaving Ser. No. 10/460,597, filed Jun. 11, 2003, filed concurrentlyherewith, entitled “Arrhythmia Discrimination”, to Shelchuk, which isincorporated by reference herein and which claims priority to a U.S.Provisional Application having Ser. No. 60/388,623, filed Jun. 12, 2002,which is also incorporated by reference herein.

TECHNICAL FIELD

Exemplary methods and/or devices presented herein generally relate tocardiac pacing and/or stimulation therapy. Various exemplary methodsand/or devices concern stimulating parasympathetic nerves in a patientexperiencing, or at risk of experiencing, congestive heart failure.

BACKGROUND

Congestive heart failure (CHF) is a condition that is often associatedwith a weakened heart that cannot pump enough blood to body organs. InCHF, the heart may be weakened due to hypertension, vascular disease,valvular disease, etc. Or, CHF may cause a fluid or chemical imbalancethat leads to such diseases. In either case, once a patient is diagnosedwith CHF, the disease typically worsens with time. CHF patients oftenhave elevated heart rates, which may be considered a natural physiologicresponse to maintain or increase cardiac output. Cardiac output may bedetermined by multiplying stroke volume by heart rate. Hence an increasein heart rate may increase cardiac output. However, an increase in heartrate may be detrimental to a diseased heart. In particular, thecondition of a diseased heart typically worsens in response to anincrease in heart rate. Thus, to maintain or increase cardiac output,most agree that an increase in stroke volume is preferable to anincrease in heart rate.

Traditional implantable pacing devices are often indicated for CHFpatients. Such devices typically aim to compensate for CHF bymaintaining a suitable heart rate; however, a controlled heart ratealone may do little to slow progression of CHF. Consequently, a needexists for methods and/or devices that can better address cardiac outputissues, particularly in CHF patients. As discussed below, stimulation ofparasympathetic nerves can help to address such cardiac output issues.

SUMMARY

Exemplary methods for decreasing workload, maintaining or increasingcardiac output and/or achieving a desirable autonomic balance bystimulating one or more parasympathetic nerves. Various exemplarymethods include delivering one or more stimulation pulsespostinspiration, based at least in part on detection of one or morecardiac event and/or during a refractory period. Other exemplary methodsand/or devices are also disclosed. The various exemplary methods and/ordevices described herein, and equivalents thereof, are suitable for usein a variety of pacing therapies and other cardiac related therapies.

BRIEF DESCRIPTION OF THE DRAWINGS

Features and advantages of the described implementations can be morereadily understood by reference to the following description taken inconjunction with the accompanying drawings.

FIG. 1 is a simplified diagram illustrating an exemplary implantablestimulation device in electrical communication with at least three leadsimplanted into a patient's heart and at least one other lead fordelivering stimulation and/or shock therapy.

FIG. 2 is a functional block diagram of an exemplary implantablestimulation device illustrating basic elements that are configured toprovide cardioversion, defibrillation, pacing stimulation and/orautonomic nerve stimulation. The implantable stimulation device isfurther configured to sense information and administer stimulationpulses responsive to such information.

FIG. 3 is a simplified approximate anatomical diagram of aparasympathetic pathway and a sympathetic pathway of the autonomicnervous system.

FIG. 4 is a simplified approximate anatomical diagram of sympatheticpathways and/or parasympathetic pathways to the heart.

FIG. 5 is a simplified approximate anatomical diagram of parasympatheticafferent pathways.

FIG. 6 is an approximate anatomical ventral view diagram of a humanheart including some arteries, veins and nerves.

FIG. 7 is an approximate anatomical dorsal view diagram of a human heartincluding some arteries, veins and nerves.

FIG. 8 is a block diagram of an exemplary method for responding to aneed for increased cardiac output.

FIG. 9 is a block diagram of an exemplary method for responding to anincrease in sympathetic activity.

FIG. 10 is a block diagram of an exemplary method for compensating forinadequate AV conduction.

FIG. 11 is an approximate anatomical ventral view diagram of a humanheart including some arteries, veins and nerves and stimulation leadsassociated with a pacing device.

FIG. 12 is a block diagram of an exemplary method for delivering astimulation pulse postinspiration.

FIG. 13 is a block diagram of an exemplary method for deliveringparasympathetic stimulation during a postinspiration phase and/or basedon detection of one or more cardiac events.

DETAILED DESCRIPTION

The following description is of the best mode presently contemplated forpracticing the described implementations. This description is not to betaken in a limiting sense, but rather is made merely for the purpose ofdescribing the general principles of the implementations. The scope ofthe described implementations should be ascertained with reference tothe issued claims. In the description that follows, like numerals orreference designators will be used to reference like parts or elementsthroughout.

Overview

Various exemplary methods and/or devices described herein stimulate aparasympathetic pathway in an effort to maintain or increase cardiacoutput and/or to achieve a desirable autonomic balance. The descriptionthat follows introduces an implantable stimulation device suitable foruse with various exemplary methods. Of course, other suitableimplantable devices may be used. In addition, the description includes adiscussion of physiological conditions related to cardiac output and/orCHF, which also discusses parasympathetic and sympathetic concerns.Next, physiology of the autonomic system is presented, followed by apresentation of various exemplary methods and/or devices that rely onautonomic stimulation to, at least in part, maintain or increase cardiacoutput and/or achieve a desirable autonomic balance. Various exemplarymethods may deliver parasympathetic stimulation postinspiration and/orin synchrony with various aspects of a cardiac cycle.

Exemplary Stimulation Device

The techniques described below are intended to be implemented inconnection with any stimulation device that is configured orconfigurable to stimulate nerves and/or stimulate and/or shock apatient's heart.

FIG. 1 shows an exemplary stimulation device 100 in electricalcommunication with a patient's heart 102 by way of three leads 104, 106,108, suitable for delivering multi-chamber stimulation and shocktherapy. The leads 104, 106, 108 are optionally configurable fordelivery of stimulation pulses suitable for stimulation of autonomicnerves. In addition, the device 100 includes a fourth lead 110 having,in this implementation, three electrodes 144, 144′, 144″ suitable forstimulation of autonomic nerves. This lead may be positioned in and/ornear a patient's heart or near an autonomic nerve within a patient'sbody and remote from the heart. The right atrial lead 104, as the nameimplies, is positioned in and/or passes through a patient's rightatrium. The right atrial lead 104 optionally senses atrial cardiacsignals and/or provide right atrial chamber stimulation therapy. Asshown in FIG. 1, the stimulation device 100 is coupled to an implantableright atrial lead 104 having, for example, an atrial tip electrode 120,which typically is implanted in the patient's right atrial appendage.The lead 104, as shown in FIG. 1, also includes an atrial ring electrode121. Of course, the lead 104 may have other electrodes as well. Forexample, the right atrial lead optionally includes a distal bifurcationhaving electrodes suitable for stimulation of autonomic nerves.

To sense atrial cardiac signals, ventricular cardiac signals and/or toprovide chamber pacing therapy, particularly on the left side of apatient's heart, the stimulation device 100 is coupled to a coronarysinus lead 106 designed for placement in the coronary sinus and/ortributary veins of the coronary sinus. Thus, the coronary sinus lead 106is optionally suitable for positioning at least one distal electrodeadjacent to the left ventricle and/or additional electrode(s) adjacentto the left atrium. In a normal heart, tributary veins of the coronarysinus include, but may not be limited to, the great cardiac vein, theleft marginal vein, the left posterior ventricular vein, the middlecardiac vein, and the small cardiac vein.

Accordingly, an exemplary coronary sinus lead 106 is optionally designedto receive atrial and ventricular cardiac signals and to deliver leftventricular pacing therapy using, for example, at least a leftventricular tip electrode 122, left atrial pacing therapy using at leasta left atrial ring electrode 124, and shocking therapy using at least aleft atrial coil electrode 126. For a complete description of a coronarysinus lead, the reader is directed to U.S. patent application Ser. No.09/457,277, filed Dec. 8, 1999, entitled “A Self-Anchoring, SteerableCoronary Sinus Lead” (Pianca et al.); and U.S. Pat. No. 5,466,254,“Coronary Sinus Lead with Atrial Sensing Capability” (Helland), whichare incorporated herein by reference. The coronary sinus lead 106further optionally includes electrodes for stimulation of autonomicnerves. Such a lead may include pacing and autonomic nerve stimulationfunctionality and may further include bifurcations or legs. For example,an exemplary coronary sinus lead includes pacing electrodes capable ofdelivering pacing pulses to a patient's left ventricle and at least oneelectrode capable of stimulating an autonomic nerve. An exemplarycoronary sinus lead (or left ventricular lead or left atrial lead) mayalso include at least one electrode capable of stimulating an autonomicnerve, such an electrode may be positioned on the lead or a bifurcationor leg of the lead.

Stimulation device 100 is also shown in electrical communication withthe patient's heart 102 by way of an implantable right ventricular lead108 having, in this exemplary implementation, a right ventricular tipelectrode 128, a right ventricular ring electrode 130, a rightventricular (RV) coil electrode 132, and an SVC coil electrode 134.Typically, the right ventricular lead 108 is transvenously inserted intothe heart 102 to place the right ventricular tip electrode 128 in theright ventricular apex so that the RV coil electrode 132 will bepositioned in the right ventricle and the SVC coil electrode 134 will bepositioned in the superior vena cava. Accordingly, the right ventricularlead 108 is capable of sensing or receiving cardiac signals, anddelivering stimulation in the form of pacing and shock therapy to theright ventricle. An exemplary right ventricular lead may also include atleast one electrode capable of stimulating an autonomic nerve, such anelectrode may be positioned on the lead or a bifurcation or leg of thelead.

FIG. 2 shows an exemplary, simplified block diagram depicting variouscomponents of stimulation device 100. The stimulation device 100 can becapable of treating both fast and slow arrhythmias with stimulationtherapy, including cardioversion, defibrillation, and pacingstimulation. The stimulation device can be solely or further capable ofdelivering stimuli to autonomic nerves. While a particular multi-chamberdevice is shown, it is to be appreciated and understood that this isdone for illustration purposes only. Thus, the techniques and methodsdescribed below can be implemented in connection with any suitablyconfigured or configurable stimulation device. Accordingly, one of skillin the art could readily duplicate, eliminate, or disable theappropriate circuitry in any desired combination to provide a devicecapable of treating the appropriate chamber(s) or regions of a patient'sheart with cardioversion, defibrillation, pacing stimulation, and/orautonomic nerve stimulation.

Housing 200 for stimulation device 100 is often referred to as the“can”, “case” or “case electrode”, and may be programmably selected toact as the return electrode for all “unipolar” modes. Housing 200 mayfurther be used as a return electrode alone or in combination with oneor more of the coil electrodes 126, 132 and 134 for shocking purposes.Housing 200 further includes a connector (not shown) having a pluralityof terminals 201, 202, 204, 206, 208, 212, 214, 216, 218, 221 (shownschematically and, for convenience, the names of the electrodes to whichthey are connected are shown next to the terminals).

To achieve right atrial sensing, pacing and/or autonomic stimulation,the connector includes at least a right atrial tip terminal (A_(R) TIP)202 adapted for connection to the atrial tip electrode 120. A rightatrial ring terminal (A_(R) RING) 201 is also shown, which is adaptedfor connection to the atrial ring electrode 121. To achieve left chambersensing, pacing, shocking, and/or autonomic stimulation, the connectorincludes at least a left ventricular tip terminal (V_(L) TIP) 204, aleft atrial ring terminal (A_(L) RING) 206, and a left atrial shockingterminal (A_(L) COIL) 208, which are adapted for connection to the leftventricular tip electrode 122, the left atrial ring electrode 124, andthe left atrial coil electrode 126, respectively. Connection to suitableautonomic nerve stimulation electrodes is also possible via these and/orother terminals (e.g., via a nerve stimulation terminal S ELEC 221).

To support right chamber sensing, pacing, shocking, and/or autonomicnerve stimulation, the connector further includes a right ventriculartip terminal (V_(R) TIP) 212, a right ventricular ring terminal (V_(R)RING) 214, a right ventricular shocking terminal (RV COIL) 216, and asuperior vena cava shocking terminal (SVC COIL) 218, which are adaptedfor connection to the right ventricular tip electrode 128, rightventricular ring electrode 130, the RV coil electrode 132, and the SVCcoil electrode 134, respectively. Connection to suitable autonomic nervestimulation electrodes is also possible via these and/or other terminals(e.g., via the nerve stimulation terminal S ELEC 221).

At the core of the stimulation device 100 is a programmablemicrocontroller 220 that controls the various modes of stimulationtherapy. As is well known in the art, microcontroller 220 typicallyincludes a microprocessor, or equivalent control circuitry, designedspecifically for controlling the delivery of stimulation therapy, andmay further include RAM or ROM memory, logic and timing circuitry, statemachine circuitry, and I/O circuitry. Typically, microcontroller 220includes the ability to process or monitor input signals (data orinformation) as controlled by a program code stored in a designatedblock of memory. The type of microcontroller is not critical to thedescribed implementations. Rather, any suitable microcontroller 220 maybe used that carries out the functions described herein. The use ofmicroprocessor-based control circuits for performing timing and dataanalysis functions are well known in the art.

Representative types of control circuitry that may be used in connectionwith the described embodiments can include the microprocessor-basedcontrol system of U.S. Pat. No. 4,940,052 (Mann et al.), thestate-machine of U.S. Pat. No. 4,712,555 (Thornander et al.) and U.S.Pat. No. 4,944,298 (Sholder), all of which are incorporated by referenceherein. For a more detailed description of the various timing intervalsused within the stimulation device and their inter-relationship, seeU.S. Pat. No. 4,788,980 (Mann et al.), also incorporated herein byreference.

FIG. 2 also shows an atrial pulse generator 222 and a ventricular pulsegenerator 224 that generate pacing stimulation pulses for delivery bythe right atrial lead 104, the coronary sinus lead 106, and/or the rightventricular lead 108 via an electrode configuration switch 226. It isunderstood that in order to provide stimulation therapy in each of thefour chambers of the heart (or to autonomic nerves) the atrial andventricular pulse generators, 222 and 224, may include dedicated,independent pulse generators, multiplexed pulse generators, or sharedpulse generators. The pulse generators 222 and 224 are controlled by themicrocontroller 220 via appropriate control signals 228 and 230,respectively, to trigger or inhibit the stimulation pulses.

Microcontroller 220 further includes timing control circuitry 232 tocontrol the timing of the stimulation pulses (e.g., pacing rate,atrio-ventricular (AV) delay, atrial interconduction (A-A) delay, orventricular interconduction (V-V) delay, etc.) as well as to keep trackof the timing of refractory periods, blanking intervals, noise detectionwindows, evoked response windows, alert intervals, marker channeltiming, etc., which is well known in the art.

Microcontroller 220 further includes an arrhythmia detector 234, amorphology detector 236, and optionally an orthostatic compensator and aminute ventilation (MV) response module, the latter two are not shown inFIG. 2. These components can be utilized by the stimulation device 100for determining desirable times to administer various therapies,including those to reduce the effects of orthostatic hypotension. Theaforementioned components may be implemented in hardware as part of themicrocontroller 220, or as software/firmware instructions programmedinto the device and executed on the microcontroller 220 during certainmodes of operation.

Microcontroller 220 further includes an autonomic nerve stimulationmodule 238 for performing a variety of tasks related to autonomic nervestimulation. This component can be utilized by the stimulation device100 for determining desirable times to administer various therapies,including, but not limited to, parasympathetic stimulation. Theautonomic module 238 may be implemented in hardware as part of themicrocontroller 220, or as software/firmware instructions programmedinto the device and executed on the microcontroller 220 during certainmodes of operation.

The electronic configuration switch 226 includes a plurality of switchesfor connecting the desired electrodes to the appropriate I/O circuits,thereby providing complete electrode programmability. Accordingly,switch 226, in response to a control signal 242 from the microcontroller220, determines the polarity of the stimulation pulses (e.g., unipolar,bipolar, combipolar, etc.) by selectively closing the appropriatecombination of switches (not shown) as is known in the art.

Atrial sensing circuits 244 and ventricular sensing circuits 246 mayalso be selectively coupled to the right atrial lead 104, coronary sinuslead 106, and the right ventricular lead 108, through the switch 226 fordetecting the presence of cardiac activity in each of the four chambersof the heart. Accordingly, the atrial (ATR. SENSE) and ventricular (VTR.SENSE) sensing circuits, 244 and 246, may include dedicated senseamplifiers, multiplexed amplifiers, or shared amplifiers. Switch 226determines the “sensing polarity” of the cardiac signal by selectivelyclosing the appropriate switches, as is also known in the art. In thisway, the clinician may program the sensing polarity independent of thestimulation polarity. The sensing circuits (e.g., 244 and 246) areoptionally capable of obtaining information indicative of tissuecapture.

Each sensing circuit 244 and 246 preferably employs one or more lowpower, precision amplifiers with programmable gain and/or automatic gaincontrol, bandpass filtering, and a threshold detection circuit, as knownin the art, to selectively sense the cardiac signal of interest. Theautomatic gain control enables the device 100 to deal effectively withthe difficult problem of sensing the low amplitude signalcharacteristics of atrial or ventricular fibrillation.

The outputs of the atrial and ventricular sensing circuits 244 and 246are connected to the microcontroller 220, which, in turn, is able totrigger or inhibit the atrial and ventricular pulse generators 222 and224, respectively, in a demand fashion in response to the absence orpresence of cardiac activity in the appropriate chambers of the heart.Furthermore, as described herein, the microcontroller 220 is alsocapable of analyzing information output from the sensing circuits 244and 246 and/or the data acquisition system 252 to determine or detectwhether and to what degree tissue capture has occurred and to program apulse, or pulses, in response to such determinations. The sensingcircuits 244 and 246, in turn, receive control signals over signal lines248 and 250 from the microcontroller 220 for purposes of controlling thegain, threshold, polarization charge removal circuitry (not shown), andthe timing of any blocking circuitry (not shown) coupled to the inputsof the sensing circuits, 244 and 246, as is known in the art.

For arrhythmia detection, the device 100 utilizes the atrial andventricular sensing circuits, 244 and 246, to sense cardiac signals todetermine whether a rhythm is physiologic or pathologic. In reference toarrhythmias, as used herein, “sensing” is reserved for the noting of anelectrical signal or obtaining data (information), and “detection” isthe processing (analysis) of these sensed signals and noting thepresence of an arrhythmia. The timing intervals between sensed events(e.g., P-waves, R-waves, and depolarization signals associated withfibrillation which are sometimes referred to as “F-waves” or“Fib-waves”) are then classified by the arrhythmia detector 234 of themicrocontroller 220 by comparing them to a predefined rate zone limit(i.e., bradycardia, normal, low rate VT, high rate VT, and fibrillationrate zones) and various other characteristics (e.g., sudden onset,stability, physiologic sensors, and morphology, etc.) in order todetermine the type of remedial therapy that is needed (e.g., bradycardiapacing, anti-tachycardia pacing, cardioversion shocks or defibrillationshocks, collectively referred to as “tiered therapy”).

Cardiac signals are also applied to inputs of an analog-to-digital (A/D)data acquisition system 252. The data acquisition system 252 isconfigured to acquire intracardiac electrogram signals, convert the rawanalog data into a digital signal, and store the digital signals forlater processing and/or telemetric transmission to an external device254. The data acquisition system 252 is coupled to the right atrial lead104, the coronary sinus lead 106, the right ventricular lead 108 and/orthe nerve stimulation lead through the switch 226 to sample cardiacsignals across any pair of desired electrodes.

The microcontroller 220 is further coupled to a memory 260 by a suitabledata/address bus 262, wherein the programmable operating parameters usedby the microcontroller 220 are stored and modified, as required, inorder to customize the operation of the stimulation device 100 to suitthe needs of a particular patient. Such operating parameters define, forexample, pacing pulse amplitude, pulse duration, electrode polarity,rate, sensitivity, automatic features, arrhythmia detection criteria,and the amplitude, waveshape, number of pulses, and vector of eachshocking pulse to be delivered to the patient's heart 102 within eachrespective tier of therapy. One feature of the described embodiments isthe ability to sense and store a relatively large amount of data (e.g.,from the data acquisition system 252), which data may then be used forsubsequent analysis to guide the programming of the device.

Advantageously, the operating parameters of the implantable device 100may be non-invasively programmed into the memory 260 through a telemetrycircuit 264 in telemetric communication via communication link 266 withthe external device 254, such as a programmer, transtelephonictransceiver, or a diagnostic system analyzer. The microcontroller 220activates the telemetry circuit 264 with a control signal 268. Thetelemetry circuit 264 advantageously allows intracardiac electrogramsand status information relating to the operation of the device 100 (ascontained in the microcontroller 220 or memory 260) to be sent to theexternal device 254 through an established communication link 266.

The stimulation device 100 can further include a physiologic sensor 270,commonly referred to as a “rate-responsive” sensor because it istypically used to adjust pacing stimulation rate according to theexercise state of the patient. However, the physiological sensor 270 mayfurther be used to detect changes in cardiac output (see, e.g., U.S.Pat. No. 6,314,323, entitled “Heart stimulator determining cardiacoutput, by measuring the systolic pressure, for controlling thestimulation”, to Ekwall, issued Nov. 6, 2001, which discusses a pressuresensor adapted to sense pressure in a right ventricle and to generate anelectrical pressure signal corresponding to the sensed pressure, anintegrator supplied with the pressure signal which integrates thepressure signal between a start time and a stop time to produce anintegration result that corresponds to cardiac output), changes in thephysiological condition of the heart, or diurnal changes in activity(e.g., detecting sleep and wake states). Accordingly, themicrocontroller 220 responds by adjusting the various pacing parameters(such as rate, AV Delay, V-V Delay, etc.) at which the atrial andventricular pulse generators, 222 and 224, generate stimulation pulses.

While shown as being included within the stimulation device 100, it isto be understood that the physiologic sensor 270 may also be external tothe stimulation device 100, yet still be implanted within or carried bythe patient. Examples of physiologic sensors that may be implemented indevice 100 include known sensors that, for example, sense respirationrate, pH of blood, ventricular gradient, cardiac output, preload,afterload, workload, contractility, and so forth. Another sensor thatmay be used is one that detects activity variance, wherein an activitysensor is monitored diurnally to detect the low variance in themeasurement corresponding to the sleep state. For a complete descriptionof the activity variance sensor, the reader is directed to U.S. Pat. No.5,476,483 (Bornzin et al.), issued Dec. 19, 1995, which patent is herebyincorporated by reference.

More specifically, the physiological sensors 270 optionally includesensors for detecting movement and minute ventilation in the patient.The physiological sensors 270 may include a position sensor and/or aminute ventilation (MV) sensor to sense minute ventilation, which isdefined as the total volume of air that moves in and out of a patient'slungs in a minute. Signals generated by the position sensor and MVsensor are passed to the microcontroller 220 for analysis in determiningwhether to adjust the pacing rate, etc. The microcontroller 220 monitorsthe signals for indications of the patient's position and activitystatus, such as whether the patient is climbing upstairs or descendingdownstairs or whether the patient is sitting up after lying down.

The stimulation device additionally includes a battery 276 that providesoperating power to all of the circuits shown in FIG. 2. For thestimulation device 100, which employs shocking therapy, the battery 276is capable of operating at low current drains for long periods of time(e.g., preferably less than 10 μA), and is capable of providinghigh-current pulses (for capacitor charging) when the patient requires ashock pulse (e.g., preferably, in excess of 2 A, at voltages above 2 V,for periods of 10 seconds or more). The battery 276 also desirably has apredictable discharge characteristic so that elective replacement timecan be detected.

The stimulation device 100 can further include magnet detectioncircuitry (not shown), coupled to the microcontroller 220, to detectwhen a magnet is placed over the stimulation device 100. A magnet may beused by a clinician to perform various test functions of the stimulationdevice 100 and/or to signal the microcontroller 220 that the externalprogrammer 254 is in place to receive or transmit data to themicrocontroller 220 through the telemetry circuits 264.

The stimulation device 100 further includes an impedance measuringcircuit 278 that is enabled by the microcontroller 220 via a controlsignal 280. The known uses for an impedance measuring circuit 278include, but are not limited to, lead impedance surveillance during theacute and chronic phases for proper lead positioning or dislodgement;detecting operable electrodes and automatically switching to an operablepair if dislodgement occurs; measuring respiration or minuteventilation; measuring thoracic impedance for determining shockthresholds; detecting when the device has been implanted; measuringstroke volume; and detecting the opening of heart valves, etc. Theimpedance measuring circuit 278 is advantageously coupled to the switch226 so that any desired electrode may be used.

In the case where the stimulation device 100 is intended to operate asan implantable cardioverter/defibrillator (ICD) device, it detects theoccurrence of an arrhythmia, and automatically applies an appropriatetherapy to the heart aimed at terminating the detected arrhythmia. Tothis end, the microcontroller 220 further controls a shocking circuit282 by way of a control signal 284. The shocking circuit 282 generatesshocking pulses of low (e.g., up to 0.5 J), moderate (e.g., 0.5 J to 10J), or high energy (e.g., 11 J to 40 J), as controlled by themicrocontroller 220. Such shocking pulses are applied to the patient'sheart 102 through at least two shocking electrodes, and as shown in thisembodiment, selected from the left atrial coil electrode 126, the RVcoil electrode 132, and/or the SVC coil electrode 134. As noted above,the housing 200 may act as an active electrode in combination with theRV electrode 132, or as part of a split electrical vector using the SVCcoil electrode 134 or the left atrial coil electrode 126 (i.e., usingthe RV electrode as a common electrode).

Cardioversion level shocks are generally considered to be of low tomoderate energy level (so as to minimize pain felt by the patient),and/or synchronized with an R-wave and/or pertaining to the treatment oftachycardia. Defibrillation shocks are generally of moderate to highenergy level (e.g., corresponding to thresholds in the range ofapproximately 5 J to 40 J), delivered asynchronously (since R-waves maybe too disorganized), and pertaining exclusively to the treatment offibrillation. Accordingly, the microcontroller 220 is capable ofcontrolling the synchronous or asynchronous delivery of the shockingpulses.

Physiological Heart Conditions Germane to Therapy

A brief overview of various physiological heart conditions followswherein various deleterious conditions may benefit from techniques thataim to maintain or increase cardiac output and/or achieve a desirableautonomic balance. Some of the conditions involve activation and/orsuppression of autonomic pathways. For example, some conditions areassociated with an increased sympathetic tone (e.g., hypersympatheticpatients) while others are associated with a decreased parasympathetictone (e.g., vagally depressed patients). As described further below,various exemplary methods aim to maintain or increase cardiac output inhypersympathetic, vagally depressed and/or congestive heart failure(CHF) patients. In general, such methods call for an increase inparasympathetic tone. In particular, various exemplary methods can havean effect similar to that achieved by administration of anangiotensin-converting enzyme (ACE) inhibitor, which is commonlyadministered to CHF patients. A brief discussion of CHF and otherconditions associated with workload issues follows.

Congestive Heart Failure (CHF)

Congestive heart failure (CHF) is a condition that is often associatedwith a weakened heart that cannot pump enough blood to body organs. Theamount of blood pumped often corresponds to a workload, which is often ameasure of resistance to blood flow. An increase in workload may causeand/or worsen heart failure. Heart failure may affect either the rightside, left side, or both sides of the heart. As pumping action is lost,blood may back up into other areas of the body, including the liver,gastrointestinal tract, and extremities (e.g., right-sided heartfailure), or the lungs (e.g., left-sided heart failure). Structural orfunctional causes of heart failure include high blood pressure(hypertension), valvular heart disease, congenital heart diseases,cardiomyopathy, heart tumor, and other heart diseases. Precipitatingfactors include infections with high fever or complicated infections,use of negative inotropic drugs (such as beta-blockers and calciumchannel blocker), anemia, irregular heartbeats (arrhythmias),hyperthyroidism, and kidney disease.

The New York Heart Association (NYHA) has classified heart conditioninto four classes: Class I—patients with no limitation of activities;they suffer no symptoms from ordinary activities; Class II—patients withslight, mild limitation of activity; they are comfortable with rest orwith mild exertion; Class III—patients with marked limitation ofactivity; they are comfortable only at rest; and Class IV—patients whoshould be at complete rest, confined to bed or chair; any physicalactivity brings on discomfort and symptoms occur at rest. Propertreatment of heart failure often relies on assessment of a patient'sclassification, see, e.g., Shamsham and Mitchell, “Essentials of thediagnosis of heart failure”, Am. Fam. Phys., Mar. 1, 2000 (pp.1319-1330). For example, Shamsham and Mitchell present an algorithm fordiastolic dysfunction and systolic dysfunction that references the NYHAclasses.

Hypertension, Workload, Cardiac Output and CHF

Hypertension may increase workload, decrease cardiac output and therebycause or worsen CHF. In fact, hypertension is one of the most commoncauses of CHF in the United States. Hypertension causes the heart topump blood against a higher resistance, which requires more force percontraction. The added strain often weakens the myocardium. While adecrease in parasympathetic activity and/or an increase in sympatheticactivity may lead to hypertension, diminished parasympathetic responseto high blood pressure may also be a mechanism in an increased workload.

Valvular Heart Disease, Workload, Cardiac Output and CHF

Valvular heart disease may increase workload and decrease cardiac outputby increasing resistance and/or reducing pumping efficiency of theheart, which, in turn, may cause or worsen CHF. Stenotic valves and/orregurgitant valves are often signs of valvular heart disease. Further,endocarditis may damage heart valves. Stenotic valves restrict bloodflow and thus increase the heart's workload while regurgitant valves or“leaky” valves allow pumped blood to flow back through a valve. In thelatter case, each contraction pumps less blood to the body when comparedto a heart with healthy. Endocarditis is an infection that affects heartvalves. Damage caused by endocarditis can reduce pumping efficiency.

Baroreceptor Response, Workload, Cardiac Output and CHF

In healthy individuals, baroreceptors located in the great arteriesprovide sensory information to second-order barosensitive neuronslocated in the lower brainstem. Via a number of intermediate neuralnetworks, the second-order neurons affect neurons, which, in turn,affect heart rate and vascular resistance. Thus, baroreceptor activationtypically reduces blood pressure and heart rate. However, in a CHFpatient, the baroreceptor response is often impaired. A study byKirchheim et al., “Physiology and pathophysiology of baroreceptorfunction and neuro-hormonal abnormalities in heart failure”, Basic Res.Cardiol., 93(Suppl. 1): 1-22 (1998) reported that congestive heartfailure is associated with an impairment of the vagally mediatedbaroreflex bradycardia, and, in general, a reduced vagal tone. Kirchheimet al., further reported that, in CHF patients, angiotensin II may causea decrease or withdrawal of vagal tone. Overall, Kirchheim et al.'sstudy of barorecpetor function suggests that therenin-angiotensin-system is linked to autonomic balance, or lackthereof, in congestive heart failure patients.

ACE Inhibitors, Workload, Cardiac Output and CHF

Angiotensin-converting enzyme (ACE) inhibitors are vasodilator drugsused to decrease pressure by interfering with the conversion ofangiotensin I to angiotensin II (a vasoconstrictor), thereforedecreasing peripheral vascular resistance. Various studies recommendtreatment of CHF using ACE inhibitors, see, e.g., Cohn, “Preventingcongestive heart failure”, Am. Fam. Phys., Apr. 15, 1998 (pp.1901-1907). A number of potential mechanisms have been suggested toexplain the efficacy of ACE inhibitors in preventing congestive heartfailure. According to Cohn, the simplest explanation is that ACEinhibitors reduce vascular tone and, by lowering impedance, improveemptying of the left ventricle, which reduces workload. Improved leftventricular systolic performance may also reduce the risk of symptomaticheart failure.

Cohn also reported that another suggested mechanism involves progressivestructural changes that occur in the left ventricular myocardium inpatients who develop overt heart failure. In this mechanism, myocardialremodeling is characterized by an enlargement of the chamber and anincrease in muscle mass. According to this mechanism, the chamberdilation is associated with a progressive reduction in wall motion,eventually resulting in a globally hypokinetic ventricle. ACE inhibitorshave been demonstrated to inhibit remodeling associated with theprogressive decline of ejection fraction and overt symptoms of heartfailure in both animal and human studies. One disadvantage to ACEinhibitors is that they may result in hyperkalemia (elevated levels ofpotassium in the blood).

Other disadvantages of ACE treatment were reported in a study by Frantz,“Beta blockade in patients with congestive heart failure”, PostgraduateMedicine, 108(8):103-118 (2000). Frantz noted that “while ACE inhibitorsare now a standard component of CHF therapy . . . they are not enough”.In particular, Frantz suggested the use of beta blockers in patientswith left ventricular systolic dysfunction and congestive heart failure(in NYHA classes I, II, and III), in essence, “to treat LV dysfunction,not just the CHF symptoms”. However, Frantz also noted that “heart rateof less than 60 beats per minute, symptomatic hypotension, excessivefatigue, and progressive signs and symptoms of CHF may all be indicatorsthat the beta blocker dose needs to be reduced and certainly notescalated”. Thus, patient monitoring may help achieve a proper betablocker dosage.

While a variety of other treatments exist for patients withdecompensated CHF, see, e.g., Loh, “Overview: Old and new controversiesin the treatment of advanced congestive heart failure”, J. Card. Fail.,7(2 Suppl. 1): 1-7 (2001); and Gomberg-Maitland et al., “Treatment ofcongestive heart failure”, Arch. Intern. Med., 161: 342-349 (2001), asdescribed below, exemplary autonomic nerve stimulation and/or pacingtherapies can beneficially treat CHF and/or related issues by reducingworkload, maintaining or increasing cardiac output and/or achieving adesirable autonomic balance.

Autonomic Nervous System

The autonomic nervous system includes sympathetic and parasympatheticpathways. Both pathways include afferent pathways (e.g., from an organto central neurons) and efferent pathways (e.g., postganglionic neuronsfrom ganglia to an organ) that relate to functioning of the heart. Forexample, parasympathetic efferent postganglionic neurons, whenstimulated, suppress atrial rate and contractile force,atrio-ventricular nodal conduction, and ventricular contractile force,also known as contractility or inotropy. Sympathetic efferentpostganglionic neurons, when stimulated, generally increase heart rateand increase contractility. Note that contractility is associated withthe term “inotropy”, heart rate is associated with the term“chronotropy” and conduction velocity is associated with the term“dromotropy”.

As already mentioned, the stimulation of parasympathetic nerves can actto decrease heart rate while stimulation of sympathetic nerves can actto increase heart rate. In addition, as noted by Mendelowitz, “Advancesin parasympathetic control of heart rate and cardiac function”, NewsPhysiol. Sci., 14:155-161 (1999), “when both parasympathetic andsympathetic activity are present, parasympathetic activity generallydominates” and “increases in parasympathetic activity to the heart evokea bradycardia that is more pronounced when there is a high level ofsympathetic firing”. Mendeolowitz also noted that “the release ofacetylcholine from parasympathetic neurons might act presynaptically toinhibit the release of norepinephrine from sympathetic nerve terminals”.

Regarding sympathetic stimulation, norepinephrine is released bysympathetic nerves. After its release, norepinephrine acts on thesinoatrial node (SA node) to increase the rate of diastolicdepolarization, and thereby increase heart rate, and acts on theatrioventricular node (AV node) to increase the velocity of conductionand diminish the refractory period during which the AV node isunresponsive to stimuli coming from the atrium.

Contractility (or inotropy) refers to the force or strength of cardiacmuscle contractions. Stimulation of sympathetic nerves causes activecontractility whereas Frank-Starling mechanism causes passivecontractility. Active contractility involves norepinephrine, whichincreases myocardial calcium permeability (or conductance) and henceactin/myosin crossbridge interactions. Other mechanisms may alsoaccompany the increase in calcium permeability.

In general, an increase in ventricular contractility causes an increasestroke volume, which, in turn, can increase cardiac output. Cardiacoutput (CO) depends on heart rate (HR) and stroke volume (SV) (e.g., COequals HR times SV). Changes in ventricular contractility alter the rateof force and pressure development by the ventricle and therefore changethe rate of ejection (i.e., ejection velocity). For example, an increasein contractility shifts the Frank-Starling curve, which causes areduction in end-systolic volume and an increase in stroke volume.Various exemplary methods described herein aim to increase end diastolicvolume and increase passive contractility via the Frank-Starlingmechanism. Of course, an increase in parasympathetic tone may also lowerresistance to blood flow through the body and hence decrease cardiacworkload.

Various exemplary methods described herein optionally stimulatesympathetic nerves in conjunction with parasympathetic nerves to achievea desirable autonomic balance—which may depend on respiratory and/orcardiac cycles. For examples, as described below, certain phases of therespiratory cycle may inhibit parasympathetic response andparasympathetic stimulation may be detrimental to certain phases of acardiac cycle. In turn, sympathetic stimulation may increase activecontractility of the heart. Hence, in one example, parasympatheticstimulation occurs postinspiration only and not during ventricularcontraction while sympathetic stimulation occurs during inspiration andduring ventricular contraction. In general, appropriate parasympatheticstimulation may act to increase passive contractility and reduceresistance to blood flow through the body while appropriate sympatheticstimulation may increase active contractility. Various exemplary methodsaim to reduce heart rate while achieving an desirable cardiac output.Again, an increase in heart rate may worsen a disease state; thus, insome instance, an increase in stroke volume is preferable to an increasein heart rate to achieve a desirable cardiac output.

Changes in inotropic state are particularly important during exercise.Increases in inotropic state helps to maintain stroke volume at highheart rates. Increased heart rate alone decreases stroke volume becauseof reduced time for diastolic filling (decreased end-diastolic volume).When inotropic state increases at the same time, this decreasesend-systolic volume to maintain stroke volume.

Another term used to describe cardiac operation is “cardiac workload”,which is sometimes defined as the product of systolic blood pressure andheart rate. In general, an increase in inotropy, chronotropy and/ordromotropy result in an increase in cardiac workload. Further,sympathetic activity is likely to increase cardiac workload whereasparasympathetic activity is likely to decrease cardiac workload. Again,sympathetic tone is often associated with tension and an increase inresistance to blood flow in the body while parasympathetic tone is oftenassociated with relaxation and a decrease in resistance to blood flow inthe body.

As already mentioned, the autonomic nervous system includesparasympathetic and sympathetic pathways. Referring to FIG. 3, asimplified diagram of the autonomic nervous system 300 is shown. Thesystem 300 illustrated includes a brain 304, a spinal cord 308, an organ312, a parasympathetic efferent pathway 318 and a sympathetic efferentpathway 358. The parasympathetic efferent pathway 318 includes apreganglionic cell body 320 located in the brain 304, a preganglionicaxon 324, a synaptic cleft 328, a postganglionic cell body 332, apostganglionic axon 336, and a postganglionic synaptic cleft 340proximate to the organ 312. An exemplary parasympathetic stimulusoriginates at the brain 304 and ends at the postganglionic synapticcleft 340 wherein a chemical is emitted to effect cell of the organ 312.A synaptic cleft may also be referred to as a neuroeffector junction.The sympathetic efferent pathway 358 includes a preganglionic cell body360 located in the spinal cord 308, a preganglionic axon 364, a synapticcleft 368, a postganglionic cell body 372, a postganglionic axon 376,and a postganglionic synaptic cleft 380 proximate to the organ 312. Anexemplary sympathetic stimulus originates at the spinal cord 308 andends at the postganglionic synaptic cleft 380 wherein a chemical isemitted to effect cell of the organ 312. In both pathways 318, 358,acetylcholine operates as a neurotransmitter to activate postganglionicneurons, i.e., preganglionic neurons are cholinergic. In parasympatheticpathways (e.g., the parasympathetic pathway 318), postganglionic neuronsemit acetylcholine and are therefore cholinergic. However, in manysympathetic pathways (e.g., the sympathetic pathway 358), postganglionicneurons emit norepinephrine and are therefore adrenergic. While FIG. 3shows a one to one ratio of preganglionic to postganglionic neurons,note that a preganglionic neuron generally links to more than onepostganglionic neuron, for example, in a sympathetic pathway, apreganglionic neuron to postganglionic neuron ratio may be approximately1:32. Autonomic pathways than can affect cardiac operation are describedin more detail below.

Autonomic Pathways

As already mentioned, the autonomic nervous system includes bothsympathetic and parasympathetic nerves. In general, the sympatheticnerves and parasympathetic nerves follow pathways, which, as describedin more detail below, are at times to some degree intermingled.Intermingling in the vagosympathetic trunks includes, for example,fibers having a sympathetic core surrounded by a parasympathetic vagalskin. Such “vagosympathetic” fibers may arise from one of thevagosympathetic trunks and descend into epicardial and/or endocardialfibers of the heart. Parasympathetic pathways effecting cardiacoperation include the vagus nerve, which is a member of a group ofnerves commonly referred to as the cranial nerves. Scientifically, thevagus nerve has been designated as the tenth cranial nerve. There aretwo of these mixed nerves that act to provide both motor and sensoryfunctions. Each vagus nerve contains both somatic and autonomicbranches; however, the autonomic function predominates. Vagus nerves areparasympathetic in nature making up 75% of all parasympathetic fiberspassing to the thoracic and abdominal regions of the body. As is thecase with most nerves, vagi nerves contain both efferent fibers (e.g.,to carry an impulse from its origin in the medulla obligata of the brainto a tissue or an organ), as well as afferent fibers, (e.g., to carry animpulse from a tissue or an organ back to the brain). With vagus nerves,80% of the fibers are afferent as opposed to efferent. This aids intheir active response to the many reflex actions in the body duringparasympathetic control. As a whole, the two vagus nerves are very largeand work to stimulate a great number of tissues in the body. Vagalstimulation can affect the heart, lungs, esophagus, stomach, smallintestine, liver, gall bladder, as well as the upper portions of theureters.

In general, the right and left vagus nerve pass down the neck as part ofright and left vagosympathetic trunks. The right and left vagus alsohave branches that innervate the heart and lungs. Further down, the leftvagus and the right vagus bifurcate into respective left and rightventral and left and right dorsal vagal branches which eventually join.The left and right ventral vagal branches join together to form theventral vagal trunk on the ventral esophagus while the left and rightdorsal vagal branches join together along the dorsal esophagus to formthe dorsal vagal trunks. These vagal trunks pass through the esophagealhiatus of the diaphragm and supply the stomach, small intestine, part ofthe large intestine and major cranial abdominal viscera withparasympathetic innervation. The vagus also includes the right and leftrecurrent laryngeal nerves, which are somatic, primarily motorsubdivisions of the vagus that travel down the neck as part of the rightand left vagosympathetic trunks.

Upon stimulation, a vagus nerve releases the hormone acetylcholine atits vagal endings and is, therefore, cholinergic. This is in contrastwith adrenergic systems which cause the release of epinephrine andnorepinephrine. It is the release of acetylcholine, rather than thepassing of nerve impulses that directly initiates a specific response.

Regarding the heart, parasympathetic vagi nerves are distributed toregions of the SA node and the AV node. Release of acetylcholine tothese regions typically results in both a decrease in the rate of rhythmof the SA node, as well as a decrease in the cardiac impulsetransmission into the ventricles. Consequences of these actionsgenerally include a decrease in heart rate, cardiac output, ventricularcontraction, arterial blood pressure, as well as a decrease in overallventricular pumping.

In general, the right vagus innervates the SA nodal region, the atrialmuscle and, to a much lesser degree, the AV nodal region; whereas, theleft vagus nerve innervates the SA nodal region and atrial muscle to alesser degree than it innervates the AV nodal region. Stimulation of theright vagus nerve can predominately slow the SA node rate and therebyreduces heart rate; whereas, stimulation of the left vagus nerve canproduce some slowing of the SA node, prolongation of AV conduction andpartial or total AV block.

The vagi nerves are also involved in a process known as respiratorysinus arrhythmia (RSA). As stated in Mendelowitz, “Advances inparasympathetic control of heart rate and cardiac function”, NewsPhysiol. Sci., 14:155-161 (1999), in RSA, “the heart beats more rapidlyin inspiration and slows during postinspiration and expiration”.Further, Mendelowitz noted that “cardiac vagal neurons recorded in vivoreceive inhibitory synaptic input during inspiration, which is thenfollowed by a rapid depolarization caused by excitatory synaptic inputduring postinspiration”.

Referring to FIG. 4, a block diagram of various components of theautonomic nervous system is shown. While FIG. 4 pertains primarily tosympathetic pathways, as already mentioned, intermingling of sympatheticpathways and parasympathetic pathways typically occurs to some degree atvarious points. The sympathetic nervous system, which is not part of thecentral nervous system, includes two parallel chains or trunks, a righttrunk 406 and a left trunk 406′. Each trunk includes a series of gangliawhich lie just lateral to the spinal cord 404 on each side (left andright). In general, the uppermost region of each trunk (406, 406′) hasthree cervical ganglia, which are continuous with the thoracic trunk.The cervical ganglia are known as the right and left superior cervicalganglia (408, 408′), the right and left middle cervical ganglia (412,412′) and the right and left inferior cervical ganglia (416, 416′), thelatter of which are known as a stellate ganglion if they combine with arespective first thoracic ganglion. Stellate ganglia exist inapproximately 70% to approximately 80% of the population.

Cardiac sympathetic fibers originate in intermediolateral columns of theupper five or six thoracic segments (see T1-T6 in FIG. 4) and lower oneor two cervical segments (see C5 and C6 in FIG. 4) of the spinal cord404. Sympathetic fibers enter the paravertebral chain and typicallysynapse in the cervical ganglia. Cardiac sympathetic ganglia aregenerally found close to the spinal column (paravertebral ganglia) andmay stem from both thoracic and cervical preganglionic fibers.Postganglionic cardiac sympathetic nerves originate from the left andright ganglia and usually approach the base of the heart (e.g., assuperior, middle, and inferior cardiac nerves) along the adventitialsurface of the great vessels.

Each of the superior cardiac nerves 432, 432′ arises by two or morebranches from a respective superior cervical ganglion 408, 408′, andoccasionally receives a filament from the trunk between a first and/or asecond cervical ganglia. The right superior cardiac nerve 432, at theroot of the neck, passes either in front of or behind the subclavianartery, and along the innominate artery to the back of the arch of theaorta, where it joins the deep part 428, 428′ of the epicardial plexus420. The right superior cardiac nerve 432 connects with othersympathetic branches. About the middle of the neck the right superiorcardiac nerve 432 receives filaments from the external laryngeal nerve;lower down, one or two twigs from the vagus; and as it enters the thoraxit is joined by a filament from the recurrent nerve. In addition,filaments from the nerve communicate with the thyroid branches from theright middle cervical ganglion 412. The left superior cardiac nerve432′, in the thorax, runs in front of the left common carotid artery andacross the left side of the arch of the aorta, to the superficial part424 of the epicardial plexus 420.

Each of the middle cardiac nerves 436, 436′ (or great cardiac nerves),the largest of the three cardiac nerves, arises from a respective middlecervical ganglion 412, 412′, or from a respective trunk 406, 406′between the middle ganglion 412, 412′ and the inferior ganglion 416,416′. On the right side, the right middle cardiac nerve 436 descendsbehind the common carotid artery, and at the root of the neck runseither in front of or behind the subclavian artery; it then descends onthe trachea, receives a few filaments from the recurrent nerve, andjoins the right half of the deep part 428 of the epicardial plexus 420.In the neck, it communicates with the right superior cardiac nerve 432and recurrent nerve. On the left side, the left middle cardiac nerve436′ enters the chest between the left carotid and subclavian arteries,and joins the left half of the deep part 428′ of the epicardial plexus420.

Each inferior cardiac nerve 440, 440′ arises from the respectiveinferior cervical ganglion 416, 416′ or the first thoracic ganglion (orstellate ganglion, e.g., 416, 416′). Both right and left inferiorcardiac nerves 440, 440′ descend behind the subclavian artery and alongthe front of the trachea, to join the deep part 428, 428′ of theepicardial plexus 420. Each of the inferior cardiac nerves 440, 440′communicates freely behind the subclavian artery with the recurrentnerve and the respective middle cardiac nerve 436, 436′.

As already mentioned with reference to FIG. 4, at the base of the heart,the sympathetic fibers form an epicardial plexus 420 that distributesthe fibers to the various regions of the heart. The epicardial plexus420 has a superficial part 424 and a deep part (shown as a right deeppart 428 and a left deep part 428′ in FIG. 4), see, e.g., Gray'sanatomy: the anatomical basis of medicine and surgery, 38th ed. (1995).The deep part 428, 428′ lies upon the tracheal bifurcation (at the backof the aorta and in front of the tracheal bifurcation) and consists ofcardiac branches from all cervical sympathetic ganglia of both right andleft sides except the superior left 408′, together with superior andinferior cervical and thoracic cardiac branches of the right vagus nerve(parasympathetic) and superior cervical and thoracic branches of theleft vagus nerve (parasympathetic).

Referring to FIG. 5, an approximate anatomical diagram of afferent vagalparasympathetic pathways 520, 520′ is shown. Vagal afferent pathwaysinclude baroreceptors and/or chemoreceptors from the aortic arch 504,carotid arteries 508, 508′ and the heart 502. With respect to the heart502, vagus afferent pathways are known to have receptors associated withatria, ventricles, pulmonary arteries and coronary arteries. Also shownin FIG. 5 are the glossopharyngeal nerves 530, 530′ and sinus branchesthereof 532, 532′. In general, such afferent pathways lead to thenucleus tractus solitarius in the brainstem. In addition, stimulation ofsuch afferent pathways typically leads to a depressor response. However,a controversial and seemingly undocumented (in humans) reflex known asthe “Bainbridge reflex” can increase heart rate due to an increase ofthe right atrial pressure. In general, cardiac receptors that lead to aneural response are classified as “A” or “B” receptors. B receptors arethe predominant stretch receptors and are stimulated by passive stretchof the atria usually during later diastole. B receptors, whenstimulated, cause a response similar to baroreceptors, e.g., inhibitionof sympathetic nerves and/or excitation of parasympathetic nerves.

Another group of receptors known as left atrial volume receptors respondto increases in transmural pressure: e.g. from increased left atrialvolume. Impulses transmitted to the osmoregulatory centers of thehypothalamus result in reduced ADH (antidiuretic hormone, vasopressin)secretion thereby increasing body water loss. Reflex hypotension andbradycardia sometimes follow left atrial distention. With hemorrhage anddecreases in left atrial pressure, ADH secretion is increased to inducewater retention. Receptors can also cause hormone secretion. Forexample, mammalian atria have secretory granules containing a smallpeptide, atrial natriuretic peptide (ANP). ANP is secreted on stretch ofthe atria. This potent, short lived peptide induces renal secretion ofsodium and increase diuresis thus serving to decrease volume. ANPappears to act to decrease CO by decreasing systemic resistance and byincrease capillary filtration.

Ventricular, mostly left ventricle, responses include the Bezold-JarishReflex, which results from ventricular wall distention stimulatingventricular mechanoreceptors. Such receptors appear to be active onlywith extreme conditions to protect the ventricle from volume overload(elicit hypotension and bradycardia). The response is a reflex vagalslowing of the heart and simultaneous inhibition of sympathoadrenalactivity. The reflex protects against cardiac overstrain, pulmonaryedema, and hypovolemia whenever cardiac distention is excessive (e.g.,in some CHF patients). The reflex, transmitted by afferent vagal fibers,is thought to exert its sympathetic block via release of endogenousopioids likely acting on the delta-type opioid receptors in the brain.

Epicardial Autonomic Pathways

Pauza et al., “Morphology, distribution, and variability of theepicardiac neural ganglionated subplexuses in the human heart”, TheAnatomical Record 259(4): 353-382 (2000), reported that the epicardialplexus forms seven subplexuses: (I) left coronary, (II) right coronary,(III) ventral right atrial, (IV) ventral left atrial, (V) left dorsal,(VI) middle dorsal, and (VII) dorsal right atrial. Pauza et al., statethat, in general, the human right atrium is innervated by twosubplexuses (III, VII), the left atrium by three subplexuses (IV, V,VI), the right ventricle by one subplexus (II), and the left ventricleby three subplexuses (I, V, VI). Pauza et al., also note that diagramsfrom Mizeres, “The cardiac plexus in man”, Am. J. Anat. 112:141-151(1963), suggest that “left epicardiac subplexuses may be considered asbeing formed by nerves derived from the left side of the deep extrinsiccardiac plexus, whereas ventral and dorsal right atrial subplexusesshould be considered as being supplied by preganglionated nervesextending from the right vagus nerve and right sympathetic trunk, astheir branches course in the adventitia of the right pulmonary arteryand superior vena cava”. Further, Pauza et al., also state that the leftcoronary (I), right coronary (II), ventral left atrial (IV) and middledorsal (VI) subplexuses “may be considered as being formed by the deepextrinsic plexus that receives equally from both vagi and sympathetictrunks”. Note that in the Pauza et al., reference, the terms “epicardiacpreganglionated nerves” and “epicardiac postganglionated nerves” aredifferentiated from the meanings of “axons of the preganglionic andpostganglionic neurons” that are valid in the nomenclature of theautonomic nervous system, for example, as referred to above withreference to FIG. 3 and FIG. 4. Thus, the term “postganglionic neurons”includes epicardiac/epicardial preganglionic neurons as well asepicardiac/epicardial postganglionic neurons.

Neuroeffectors

Upon stimulation, end terminals (or terminal knobs) of thepostganglionic sympathetic nerves (e.g., epicardial postganglionicsympathetic nerves) release norepinephrine, which acts upon themyocardium. Following stimulation and release, norepinephrine remainsactive for several seconds; norepinephrine may then be reabsorbed by theterminal, diffuse out of the area, or be inactivated by enzymes. Theadrenal medulla also secretes norepinephrine (e.g., 75 percentepinephrine and 25 percent norepinephrine) and produces a peripheraleffect that typically lasts much longer than that produced bystimulation of the sympathetic postganglionic terminal knobs. Whilecirculating norepinephrine can increase contractility, the effect onnormally innervated hearts is relatively minor with respect tonorepinephrine released by end terminals. Heart rate, although initiallystimulated by norepinephrine, usually decreases over time due toactivation of baroreceptors and vagal-mediated (parasympathetic) slowingof the heart rate.

Cardiac tissue membrane receptors, such as alpha receptors and betareceptors, receive chemicals emitted by postganglionic nerves. Alphareceptors are the most common type of sympathetic receptor and theyrespond strongly to norepinephrine and weakly to epinephrine. Betareceptors are also adrenergic and include beta-1, beta-2 and beta-3receptors. Cardiac sympathetic receptors are mostly the beta-1 subtype.Beta-1 receptors, which respond approximately equally to norepinephrineand epinephrine, generally act on the myocardium to increase heart rate,contractility, and/or conduction velocity. In contrast, parasympatheticcholinergic muscarinic receptors act on the sinoatrial (SA) node todecrease heart rate and act on the atrioventricular (AV) node todecrease conduction velocity. Adrenergic antagonists (indirect action)include beta-blockers such as proranolol and alpha-blockers such asphentolamine that inhibit receptors. Cholinergic antagonists (indirectaction) include alpha-blockers such as atropine.

Exemplary Detection of Factors Related to Workload and/or Cardiac Output

Various exemplary methods presented below rely on detection of a need todecrease workload and/or detection of a need to maintain or increasecardiac output (e.g., by increasing passive contractility and/or activecontractility and not necessarily by increasing heart rate). Withrespect to workload, such a need may be determined using factors relatedto workload or afterload. Afterload typically increases when aorticpressure and systemic vascular resistance are increased, for example, byaortic valve stenosis, ventricular dilation (e.g., hypertrophy), etc.When afterload increases, there is an increase in end-systolic volumeand a decrease in stroke volume. Thus, if heart rate does not increase,cardiac output will drop. An increase in afterload generally decreasesvelocity of fiber shortening. Because the period of time available forejection is finite (˜150-200 msec), a decrease in fiber shorteningvelocity reduces the rate of volume ejection so that more blood is leftwithin the ventricle at the end of systole (increase end-systolicvolume).

An exemplary implantable device optionally includes a blood pressuresensor that can sense blood pressure; accordingly, if sensed bloodpressure is above a threshold value, then a need for decreased workloadmay exist. In addition, blood pressure may signal a need to maintain orincrease cardiac output by increasing stroke volume and optionallydecreasing heart rate. In this example, the sensor may sense afterloadpressure, which is the initial pressure of systole. The afterloadpressure or resistance is typically a measure of systemic vascularresistance and generally represents the sum of all forces which opposeventricular muscle shortening during systole. Of course, other factorsrelated hemodynamics may be used (e.g., flow rate, etc.).

As described, while an increase in workload may indicate a need toadjust cardiac output, a decrease in cardiac output may indicate a needto decrease workload. If myocardial function is severely depressed,cardiac output may become crucially afterload-dependent. In suchcircumstances, cardiac output may be an indicator of a need to decreaseworkload. Further, an increase in cardiac output may indicate thatworkload has decreased.

A need to decrease workload and/or to maintain or increase cardiacoutput may be based on cardiac velocity. For example, under conditionsof constant preload, the initial velocity of shortening of isolatedpapillary muscle falls progressively as afterload is increased,particularly if afterload becomes excessive.

A need to decrease workload and/or to maintain or increase cardiacoutput may also be based on cardiac electrical activity. For example,variance in R-to-R intervals may indicate when a decrease in workloadwould be beneficial. Variance in R-to-R intervals may reflect heart rateturbulence. Again, an increase in heart rate may be considered a normalphysiological response to an increase in workload or a decrease incardiac output.

Electrical and/or Magnetic Stimulation of Autonomic Nerves

Electrical stimulation of autonomic nerves has been reported in theliterature, see, e.g., Murakami et al., “Effects of cardiac sympatheticnerve stimulation on the left ventricular end-systolic pressure-volumerelationship and plasma norepinephrine dynamics in dogs”, Jpn. Circ. J.61(10): 864-71 (1997); and Du et al., “Response to cardiac sympatheticactivation in transgenic mice overexpressing beta 2-adrenergicreceptor”. Am-J-Physiol. August; 271(2 Pt 2): H630-6 (1996). Magneticstimulation of nerves has also been reported, for example, where a nerveis exposed to a time-varying magnetic field, which may induce electricalcurrents in the nerve.

According to various exemplary methods and/or devices described herein,a series of pulses, or a pulse train, is typically delivered by animplantable stimulation device to stimulate an autonomic nerve. Thepulse train optionally includes pulse parameters or pulse trainparameters, such as, but not limited to, frequency, pulse duration (orpulse width), number of pulses, and/or amplitude. These parameters mayhave broad ranges and vary over time within any given pulse train. Ingeneral, a power level for individual pulses and/or pulse trains isdetermined based on these parameters and/or other parameters. Exemplaryranges for pulse frequency include frequencies ranging fromapproximately 0.1 to approximately 50 Hz, and, in particular,frequencies ranging from approximately 1 Hz to approximately 20 Hz. Ofcourse, higher frequencies higher than 50 Hz may also be suitable.Exemplary ranges for pulse duration, or pulse width for an individualpulse (generally within a pulse train), include pulse widths rangingfrom approximately 0.01 milliseconds to approximately 5 millisecondsand, in particular, pulse widths ranging from approximately 0.1milliseconds to approximately 2 milliseconds. Exemplary pulse amplitudesare typically given in terms of current or voltage; however, a pulse ora pulse trains may also be specified by power, charge and/or energy. Forexample, in terms of current, exemplary ranges for pulse amplitudeinclude amplitudes ranging from approximately 0.02 mA to approximately20 mA, in particular, ranging from 0.1 mA to approximately 5 mA.Exemplary ranges for pulse amplitude in terms of voltage includevoltages ranging from approximately 1 V to approximately 50 V, inparticular, ranging from approximately 1 V to approximately 15 V.

For pulses delivered by implantable stimulation devices having a fixedor otherwise limited power supply, i.e., a power supply having powerlimitations, average power of a pulse or a pulse train is usuallylimited acutely by the power capability of the power supply (e.g.,battery, fuel cell, nuclear generator, etc.) and chronically by thecapacity of the power supply and desired longevity of the device'susefulness. Average power of a pulse is generally given as peak poweraveraged over one cycle. For example, given a voltage of 10 V, aresistance of 1000 ohms, a pulse frequency of 20 Hz and a pulse width of1 ms, the peak power is given as voltage squared divided by resistance,which is 0.1 W, and the average power is 20 Hz multiplied by 1 msmultiplied by 0.1 W, which is 0.002 W or 2 mW. The term “power”, as usedherein, includes, but is not limited to, peak power and average power.

Current drain is another factor often considered when determining powerlimitations of a power supply. Current drain is generally defined as theaverage amount of current drawn from a power supply in an implantablepulse generator in one hour. Current drain depends on many factors,including how frequently the device delivers pulses and at whatparameters, the circuitry and/or the type of stimulation lead. Currentdrain is commonly expressed in millionths of an ampere or microamperes.A power drain based on current drain may be determined by the product ofcurrent drain and voltage. Such a power is optionally useful indetermining a maximum power level for an autonomic stimulation pulse orpulses.

In general, a maximum power level or maximum power demand for animplantable device may be determined, in part, by the product of thevoltage times the current capability of the battery (or other powersupply) less circuit inefficiencies. Of course, desired power supplylife (e.g., battery life) and/or other factors may be considered. Forexample, some implantable stimulation devices have a continuous powerdrain for one function (e.g., to drive a microchip, microprocessor ortiming circuitry) and an intermittent function (e.g., such as pacing,measuring, signaling, etc.) which has intermittent power utilization.Consideration of such factors may be necessary in determining atolerable and/or maximum power level and, in particular, in determiningpulse parameters for autonomic nerve stimulation.

Vessels and Stimulation of Autonomic Pathways

According to various exemplary methods and stimulation devices describedherein, and equivalents thereof, stimulation of parasympathetic nervesallows for influence of cardiac activity. For example, various exemplarymethods and corresponding stimulation devices rely on placement of oneor more electrodes in a vessel, e.g., an epicardial vein or anepicardial venous structure. Suitable epicardial veins or venousstructures include the coronary sinus and veins that drain into thecoronary sinus, either directly or indirectly. For example, the greatcardiac vein passes along the interventricular sulcus, with the anteriorinterventricular coronary artery, and empties anteriorly into thecoronary sinus; and the middle cardiac vein travels with the posterior(right) interventricular coronary artery and empties into the coronarysinus posteriorly. Other suitable veins include those that drain intothe right atrium or right auricle. For example, the anterior cardiacvein passes through the wall of the right atrium and empties into theright atrium.

Other exemplary methods and/or devices rely on placement of one or moreelectrodes in a non-epicardial vein. Such exemplary methods and/ordevices are optionally suitable for stimulation of parasympatheticnerves at locations, for example, generally along a parasympatheticpathway between the heart and brain. Further, other exemplary methodsand/or devices rely on placing one or more electrodes through the wallof a vein and proximate to a parasympathetic nerve.

Referring to FIG. 6, a ventral diagram of a human heart 602 is shown.Various anatomical features of the heart 602 are also shown and includean opening to the superior vena cava 606, an opening to the aorta 610,an opening to the pulmonary trunk 614, an opening to the right superiorpulmonary vein 618, an opening to the left inferior pulmonary vein 622,and an opening to the left superior pulmonary vein 626. FIG. 6 alsoshows some of the epicardial arteries (thick dashed lines) and veins(thick solid lines). Under normal conditions, epicardial arteries carryoxygenated blood to the myocardium, primarily myocardium of theventricles while epicardial veins carry blood deoxygenated by themyocardium to the right atrium of heart 602. Pressure in the veins isgenerally, on average, much less than pressure in the arteries.

Two major epicardial arterial networks are shown in FIG. 6 andassociated with the left coronary artery 630 and the right coronaryartery 634. The left coronary artery 630 stems from the aorta near theopening to the aorta 610 and travels along the base of the leftventricle where it branches. One branch of the left coronary arterytravels on the epicardial surface of the left ventricle toward the apexof the heart 602 (known as the left anterior descending artery) whileanother branch travels on the epicardial surface of the left ventricletoward the dorsal side of the heart 602 (known as the circumflex branchof the left coronary artery). The right coronary artery 634 stems fromthe aorta near the opening to the aorta 610 and travels along the baseof the right ventricle where it branches. Various branches of the rightcoronary artery 634 travel on the epicardial surface of the rightventricle while at least one branch travels on the epicardial surface ofthe right ventricle toward the dorsal side of the heart 602.

Three major epicardial venous networks are shown in FIG. 6, which areassociated with the great cardiac vein 638, the anterior cardiac vein642, and the small cardiac vein 646. The great cardiac vein 638 receivesblood from a network that spreads across the ventral side of theepicardial surface of the left ventricle and major branches of thenetwork extend toward the apex of the heart 602. As already mentioned,the great cardiac vein 638 travels on the epicardial surface near thebase of the left ventricle to the dorsal side of the heart 602 where itjoins the coronary sinus vein. The anterior cardiac vein 642 receivesblood from a network that spreads across the ventral and dorsal sides ofthe epicardial surface of the right ventricle and major branches of thenetwork extend toward the apex of the heart 602. As already mentioned,the anterior cardiac vein empties into the right atrium of the heart602. The small cardiac vein 646 travels from the ventral epicardialsurface to the dorsal epicardial surface where it empties into thecoronary sinus.

FIG. 6 also shows the seven subplexuses as identified by Pauza et al.Preganglionate nerves enter the left coronary subplexus (I) and theright coronary subplexus (II) approximately between the opening to theaorta 610 and the opening to the pulmonary trunk 614. Preganglionatenerves enter the ventral right atrial subplexus (III) at the superiorinteratrial sulcus and non-regularly on the ventral surface of the rootof the superior vena cava while preganglionated nerves enter the ventralleft atrial subplexus (IV) approximately between the superiorinteratrial sulcus and left atrial nerve fold. Preganglionated nervesenter the left dorsal subplexus (V) approximately at the left atrialnerve fold and preganglionated nerves enter the middle dorsal subplexus(VI) approximately between the right and left superior pulmonary veins(see, e.g., 618, 626) and, non-regularly, between the right pulmonaryveins and the inferior vena cava. Preganglionated nerves enter thedorsal right atrial subplexus (VII) approximately between the superiorvena cava and the right superior pulmonary vein (see, e.g., 606, 618).As already mentioned, postganglionated nerves, and some preganglionatednerves, spread out from the subplexuses (I-VII) across the epicardialsurface of the heart 602. The spreading of such nerves is shown by thethick solid arrows in FIG. 6 and FIG. 6, the latter of which shows adorsal diagram of the heart 602.

Referring to FIG. 7, a dorsal diagram of the human heart 602 is shown.Various anatomical features of the heart 602 are also shown and includean opening to the superior vena cava 606, an opening to the inferiorvena cava 624, an opening to the right inferior pulmonary vein 628, andan opening to the left inferior pulmonary vein 622. FIG. 7 also showssome of the epicardial arteries (thick dashed lines) and veins (thicksolid lines). The arterial and venous networks shown on the dorsalepicardial surface of the heart 602 include extensions of networks fromthe ventral epicardial surface. For example, the dorsal epicardialsurface includes networks stemming the right coronary artery 634 and theleft coronary artery 630. In particular, the circumflex branch of theleft coronary artery 630 is shown along with various extensions of theright coronary artery 634 one of which approaches the end of thecircumflex branch. Venous epicardial structures shown in FIG. 6 includethe coronary sinus 662, the great cardiac vein 638, the small cardiacvein 646, the oblique vein of the left atrium 652, the left marginalvein 650, the posterior vein of the left ventricle 654, and the middlecardiac vein 658. The aforementioned veins (638, 646, 650, 652, 654,658) empty into the coronary sinus 662.

FIG. 7 also shows, via thick solid arrows, neural extensions of five ofthe subplexuses as identified by Pauza et al. Neural extensions of theleft coronary subplexus (I) descend toward the apex of the heart 602 atand/or near the left marginal vein 650 and the posterior vein of theleft ventricle 654. Neural extensions of the right coronary subplexus(II) traverse the heart 602 at and/or near the right coronary sulcus.Neural extensions of the left dorsal subplexus (V) descend toward theapex of the heart 602 at and/or near the posterior vein of the leftventricle 654 while neural extensions of the middle dorsal subplexus(VI) descend towards the apex of the heart 602 at and/or near the middlecardiac vein 658 and the small cardiac vein 646. Neural extensions ofthe dorsal right atrial subplexus (VII) extend around the right atriumat and/or near the superior vena cava (see, e.g., 606) and the inferiorvena cava (see, e.g., 624).

As shown in FIGS. 6 and 7, various epicardial veins or venous structurestravel at and/or near epicardial subplexuses and/or epicardialextensions of epicardial subplexuses. According to various exemplarymethods and/or stimulation devices described herein, at least oneelectrode is placed in the lumen of an epicardial vein or venousstructure and/or through the wall of an epicardial vein or venousstructure. Further, upon passing current through the at least oneelectrode, neural stimulation occurs, which preferably causes release ofa neuroeffector, such as, but not limited to, acetylcholine.

Stimulation of Non-Epicardial Parasympathetic Pathways

A study by Sokolavas et al., “Surgical parasympathetic AV nodedenervation in a canine model: anatomical and electrophysiologicalstudies”, HeartWeb, 2(1), No. 96110010 (1996), concluded that “only theparasympathetic nerve fibers reach the AV node over the left dorsal andthe middle septal nerve subplexuses”. In humans, these two subplexusescorrespond to the left dorsal (V) and the middle dorsal (VI)subplexuses. Sokolavas et al., reached their conclusion, in part,through stimulation of the left vagosympathetic trunk. In particular,Sokolavas et al., placed a silver electrode on the left vagosympathetictrunk and delivered rectangular stimulation pulses having a frequency of30 Hz, a duration of 1 ms and a potential of 0.5 V to 2 V. Such pulseswere able to eventually produce a first degree AV block.

Various Exemplary Methods and/or Devices

Referring to FIG. 8, an exemplary method 800 involves positioning one ormore electrodes, for example, proximate to the left vagosympathetictrunk and/or a branch thereof and delivering a stimulation pulse to theone or more electrodes to thereby stimulate a parasympathetic nerve.More specifically, in a detection block 804, a need for increasedcardiac output is detected. Such a need may be detected based oninformation from a sensor, from a patient, from a physician, etc. Forexample, a patient may experience weight gain due to excessive fluidretention, which is a condition that may indicate a need for increasedcardiac output. In a stimulation block 808, a stimulation pulse orpulses stimulate a parasympathetic nerve in response to the detectedneed for increased cardiac output. A decision block 812 follows thatdetermines if the parasympathetic stimulation has caused a sufficientincrease in cardiac output, for example, via an increased end diastolicvolume and a resulting increase in passive contractility (e.g.,Frank-Starling mechanism). If the decision block 812 determines thatthere is no increase or an insufficient increase, then the method 800continues at an adjustment block 820. The adjustment block 820 adjustsone or more parameters associated with the stimulation of thestimulation block 808. In this instance, at the stimulation block 808,stimulation either continues or repeats using the one or more adjustedparameters.

In the case that the decision block 812 determines that there is asufficient increase in cardiac output, the method 800 may continue atanother decision block 816, which determines if ventricular pacing isavailable. If ventricular pacing is available, then the exemplary method800 may initiate ventricular pacing at a ventricular pacing block 824wherein the pacing occurs at an appropriate reduced rate. Again, a goalof various exemplary methods or devices described herein is to reduceheart rate while maintaining sufficient cardiac output. In diseasedhearts, low stroke volume is often compensated for by an elevation inheart rate in an effort to achieve a suitable cardiac output. Such acourse typically worsens the disease state; whereas, the exemplarymethod 800 aims to maintain or increase cardiac output by increasingstroke volume and not heart rate.

An exemplary device suitable for implementing the exemplary method 800may include a lead having one or more electrodes positionable proximateto the left vagosympathetic trunk and/or a branch thereof and hardwareand/or software configured to deliver a stimulation pulse to the one ormore electrodes. The exemplary method and/or device optionally deliver astimulation pulse postinspiration and/or in synchrony with one or morecardiac events. In this example, such a device and method may evenresult in some degree of AV block if ventricular pacing is available. Ofcourse, in instances where ventricular pacing is not available,induction of any significant AV block should be avoided.

FIG. 9 shows an exemplary method 900 wherein AV conduction is taken intoconsideration. In a detection block 904, a need for increased cardiacoutput is detected. Such a need may be detected based on informationfrom a sensor, from a patient, from a physician, etc. In a stimulationblock 908, a stimulation pulse or pulses stimulate a parasympatheticnerve in response to the detected need for increased cardiac output. Adecision block 912 follows that determines if there is adequate AVconduction, for example, that AV nodal filtering of atrial activationwavefronts does not exceed a set limit (e.g, 2:1, etc.). If the decisionblock 912 determines that AV conduction is inadequate, then anadjustment block 920 adjusts one or more parasympathetic stimulationparameters in a manner that aims to restore AV conduction to an adequatestate. In FIG. 9, a minus sign indicates negative feedback. If thedecision block 912 determines that there is adequate AV conduction, thenthe method 900 continues in another decision block 916 that determineswhether the stimulation resulted in a sufficient increase in cardiacoutput.

If the decision block 916 determines that no increase or an insufficientincrease in cardiac output results, then the method 900 continues in theadjustment block 920; however, in this instance, there is positivefeedback, as indicated by the plus sign. Of course, a situation mayexist wherein the increase is more than sufficient or desired andnegative feedback is sent to the adjustment block. In general,parasympathetic stimulation power or duty cycle may be ramped up in amanner to avoid such an overshoot. If the decision block 916 determinesthat the increase was sufficient, then the method 900 may return to thedetection block 904, which may monitor cardiac output to see if anysubsequent increases are needed. As in the exemplary method 800, theparasympathetic stimulation aims to cause a sufficient increase incardiac output, for example, via an increased end diastolic volume and aresulting increase in passive contractility (e.g., Frank-Starlingmechanism).

FIG. 10 shows another exemplary method 1000 which optionally implementsventricular pacing to overcome inadequate AV conduction. In a detectionblock 1004, an increase in sympathetic tone, activity, etc. is detected.Such detection may be based on information from a sensor, from apatient, from a physician, etc. In a stimulation block 1008, astimulation pulse or pulses stimulate a parasympathetic nerve inresponse to the detected increase in sympathetic tone (e.g., typicallyan increase that is not offset by an increase in parasympathetic tone).A decision block 1012 follows that determines if there is adequate AVconduction, for example, that AV nodal filtering of atrial activationwavefronts does not exceed a set limit (e.g, 2:1, etc.). If the decisionblock 1012 determines that AV conduction is inadequate, then animplementation block 1016 implements ventricular pacing. Of course, anexemplary method may include options of adjusting one or moreparasympathetic stimulation parameters and/or implementing ventricularpacing, where available.

As shown in FIG. 10, the exemplary method 1000 implements ventricularpacing to overcome inadequate AV conduction. If the decision block 1012determines that AV conduction is adequate, then the method 1000continues in another decision block 1020, which determines if autonomicbalance is sufficient. If autonomic balance is not sufficient, forexample, too little or too much parasympathetic tone, then the method1000 continues in an adjustment block 1024 that adjusts one or morestimulation parameters in an effort to achieve a sufficient autonomicbalance. The method 1000 may continue in the stimulation block 1008wherein parasympathetic stimulation continues or repeats using the oneor more adjusted parameters. Of course where too much parasympathetictone exists, a wait block, a sympathetic stimulation block or anotherblock may occur. In the exemplary method 1000, the decision block 1020typically provides positive feedback to the adjustment block 1024,especially wherein parasympathetic stimulation power and/or duty cycleare ramped up over time.

Yet another exemplary method involves stimulation of afferentparasympathetic nerves. A study by Kawada et al., “Vagosympatheticinteractions in ischemia-induced myocardial norepinephrine andacetylcholine release”, Am. J. Physiol. Heart Circ. Physiol.,280:H216-H221 (2001), reported that, in animals subject to occlusion oftheir left anterior descending coronary artery, a resulting increase insympathetic activity was diminished by vagal afferent activity. Inparticular, vagal afferent activity reduced ischemia-induced myocardialnorepinephrine release.

An exemplary device for implementing such an exemplary method mayinclude a lead having one or more electrodes positionable proximate to avagal afferent nerve and hardware and/or software configured to delivera stimulation pulse to the one or more electrodes. The exemplary methodand/or device optionally deliver a stimulation pulse postinspirationand/or in synchrony with one or more events in a cardiac cycle. Adesirable effect of such an exemplary method and/or device is to reducemyocardial norepinephrine release and/or concentrations, which may, inturn, allow parasympathetic effects to increase end diastolic volume andpassive contractility.

An exemplary method optionally adjusts parasympathetic stimulation power(e.g., amplitude, frequency, duty, etc.) as a function of heart rate.For example, if an increase in heart rate occurs, an increase inparasympathetic stimulation power duty may occur in an effort toincrease stroke volume, decrease workload, and/or maintain or increasecardiac output. In another example, an increase in cardiac output orstroke volume (e.g., end diastolic volume) may cause a decrease instimulation power.

In another exemplary method, parasympathetic stimulation halts after aperiod of time. For example, a physician may wish to see the effects ofparasympathetic stimulation on a patient. Thus, such an exemplary methodmay halt parasympathetic stimulation after one month. The physician maythen examine the course of the patient's condition post-parasympatheticstimulation to determine if the condition worsens or the rate at whichit returns to a pre-parasympathetic stimulation period state. Of course,an exemplary device may optionally include an algorithm for suchdiagnostics. Further, such an algorithm may include comparing currentresults to past results. Yet further, such an algorithm may reinitiateparasympathetic stimulation based on the comparing or some other basis(e.g., time, measurement, etc.).

Stimulation of Epicardial Parasympathetic Pathways

Referring again to FIGS. 6 and 7, various epicardial vessels are shownalong with various subplexuses. FIG. 11 is an approximate anatomicaldiagram of a ventral view of a heart that corresponds to the diagram ofFIG. 6. In FIG. 11, exemplary leads having exemplary electrodes are alsoshown in exemplary epicardial locations. For example, FIG. 11 shows theexemplary stimulation device 100 of FIG. 1 having four leads 104, 106,108, 110. The leads 104, 106, 108, 110 optionally include branches orbifurcations. In this example, any of the leads may carry electrodessuitable for stimulation of autonomic nerves. As shown in FIG. 11, oneexemplary lead 110 has an electrode portion having three electrodes 144,144′, 144″. The electrode portion of the lead 110 passes through thewall of the anterior cardiac vein 642 and extends along nerves emanatingfrom the VRA (III) subplexus. Having an electrode portion of a leadpositioned as such, activation of at least one of the electrodes 144,144′, 144″ optionally stimulate nerves to affect operation of the SAnode.

In a similar manner, another exemplary lead 110′ has an electrodeportion having three electrodes 145, 145′, 145″. The electrode portionof the lead 110′ passes through the wall of the great cardiac vein 638and extends along nerves emanating from the LD (V) subplexus. Having anelectrode portion of a lead positioned as such, activation of at leastone of the electrodes 145, 145′, 145″ optionally stimulate nerves toaffect operation of the AV node. Yet another exemplary lead 110″ has anelectrode portion having three electrodes 146, 146′, 146″. The electrodeportion of the lead 110″ passes through the wall of the superior venacava (see, e.g., opening of superior vena cava labeled 606) and extendsto the VRA (III) subplexus and/or DRA (VII) subplexus. Having anelectrode portion of a lead positioned as such, activation of at leastone of the electrodes 146, 146′, 146″ optionally stimulate nerves toaffect operation of the SA node. Of course, the locations and functionsof the three leads 110, 110′, 110″ are only exemplary as a variety ofother arrangements are possible. In general, leads may extend topre-ganglionated field regions, ganglionated field regions and/orpost-ganglionated field regions. More specifically, leads optionallyextend to pre-ganglionated field regions, ganglionated field regionsand/or post-ganglionated field regions associated with at least one ofthe seven subplexus identified in the Pauza et al. reference. While theleads shown in FIG. 11 include electrode portions that extend through avessel and/or chamber wall, other exemplary leads include electrodeportions that remain within the lumen of a vessel and/or within achamber of the heart. In addition, referring to FIG. 7, similar leadsare optionally used that may extend to pre-ganglionated field regions,ganglionated field regions and/or post-ganglionated field regions on,for example, the dorsal side of the heart. Again, such leads optionallyextend to pre-ganglionated field regions, ganglionated field regionsand/or post-ganglionated field regions associated with at least one ofthe seven subplexus identified in the Pauza et al. reference. Further,exemplary leads optionally include electrode portions that remain withinthe lumen of a vessel and/or within a chamber of the heart.

Another exemplary method involves stimulation of afferentparasympathetic nerves. As already mentioned, the study by Kawada etal., “Vagosympathetic interactions in ischemia-induced myocardialnorepinephrine and acetylcholine release”, Am. J. Physiol. Heart Circ.Physiol., 280:H216-H221 (2001), reported that, in animals subject toocclusion of their left anterior descending coronary artery, a resultingincrease in sympathetic activity was diminished by vagal afferentactivity. In particular, vagal afferent activity reducedischemia-induced myocardial norepinephrine release. An exemplary methodoptionally includes positioning of one or more electrodes, via a vein,proximate to an epicardial and/or endocardial vagal afferent nerve anddelivering a stimulation pulse to the one or more electrodes to therebystimulate the vagal afferent nerve. An exemplary device includes a leadhaving one or more electrodes positionable, via a vein, proximate to anepicardial and/or endocardial vagal afferent nerve and hardware and/orsoftware configured to deliver a stimulation pulse to the one or moreelectrodes. The exemplary method and/or device optionally deliver astimulation pulse postinspiration. A desirable effect of the exemplarymethod and/or device is to reduce myocardial norepinephrine releaseand/or concentrations, which, in turn, may allow parasympathetic tone toincrease end diastolic volume and passive contractility.

According to such an exemplary method and/or device, one or moreelectrodes are positioned and/or positionable in an epicardial veinand/or chamber of the heart. In particular, one or more electrodes areoptionally positioned proximate to an atrial vagal afferent nerve and/ora ventricular vagal afferent nerve. Further, during positioning, avariety of locations may be examined to determine which locationsproduces a more pronounced and/or desirable response.

Various exemplary methods optionally include positioning one or moreelectrodes in the superior vena cava (SVC), the inferior vena cava (IVC)and/or the coronary sinus (CS). Various exemplary methods optionallyinclude positioning one or more electrode in the azygous vein. Suitableelectrode portions for positioning electrodes in or near a nerve and/orthe heart include, but are not limited to, basket type or double helixtype of electrode portions, see, e.g., U.S. patent application havingSer. No. 10/321,307, filed Dec. 16, 2002, entitled “Implantable lead andelectrode portion”, to Helland and Shelchuk, which is incorporated byreferenced herein, and U.S. patent application having Ser. No.10/000,333, filed Oct. 22, 2001, entitled “Implantable lead and methodfor stimulation the vagus nerve”, to Weinberg, which is incorporated byreference herein.

In various exemplary methods, parasympathetic stimulation aims tostimulate a parasympathetic nerve and to avoid producing an evokedresponse from the myocardium. In this regard, parasympatheticstimulation may occur according to a power, frequency, duty cycle, phase(e.g., monophasic, biphasic, triphasic, etc.) that reduces the risk ofmyocardial stimulation and/or parasympathetic stimulation may occurduring a refractory period of the myocardium to reduce the risk ofmyocardial stimulation.

Determining Vagal Tone and/or Inspiration/Postinspiration

As already mentioned, Mendelowitz noted that “cardiac vagal neuronsrecorded in vivo receive inhibitory synaptic input during inspiration,which is then followed by a rapid depolarization caused by excitatorysynaptic input during postinspiration”. Therefore, for a variety ofreasons, the aforementioned exemplary methods and/or device optionallystimulate parasympathetic nerves postinspiration, i.e., not duringinspiration. Referring to FIG. 12, an exemplary method 1200 for deliveryof one or more stimulation pulses postinspiration is shown. In amonitoring block 1204, a stimulation and/or other device monitorsdirectly and/or indirectly heart rate. Next, in a detection block 1208,the stimulation and/or other device detects respiratory sinusarrhythmia. Following detection, in a determination block 1212, thestimulation and/or other device determines a period associated withinspiration. Next, in a delivery block 1216, the stimulation devicedelivers a stimulation pulse to a parasympathetic nerve. Also note thatsuch a method can determine a patient's vagal tone.

In another exemplary method, a stimulation and/or other device monitorsinspiration directly and/or indirectly through use of a ventilationmodule and/or sensor (e.g., impedance, etc.). In this exemplary methodand the aforementioned method, parasympathetic stimulation pulsedelivery during postinspiration only can decrease power demand on animplantable stimulation device. In yet another exemplary method,parasympathetic stimulation pulse delivery occurs during a refractoryperiod to avoid stimulation of cardiac and/or other tissue. Of course,an exemplary combined method optionally includes delivery of aparasympathetic stimulation pulse postinspiration in a refractoryperiod.

Parasympathetic Stimulation Postinspiration and/or Synchronous withHeart

As already mentioned, parasympathetic stimulation may occurpostinspiration (e.g., not during inspiration) and/or in synchrony withone or more cardiac events (e.g., events typically found in a cardiaccycle). FIG. 13 shows an exemplary method 1300 wherein parasympatheticstimulation occurs according to respiratory cycle and/or according toone or more events in a cardiac cycle. Various exemplary methodspresented herein may implement one or more of the blocks or proceduresdescribed with reference to the exemplary method 1300.

A start block 1304 may occur at anytime an exemplary method desires toimplement parasympathetic nerve stimulation. A decision block 1308follows that determines whether a patient is in a postinspiration phaseof a respiratory cycle. For example, an exemplary device may detectimpedance, movement of an implanted device, pressure, cardiaccharacteristics, autonomic tone, etc., and then use such information todetermine one or more phases of a respiratory cycle. In the exemplarymethod 1300, if the decision block 1308 determines that a patient is notin a postinspiration phase, then the method 1300 may continue in a waitblock 1316, which either causes an appropriate delay or waits for anevent indicative of a postinspiration phase. If the decision block 1308determines that a patient is in a postinspiration phase, the method 1300continues in a ventricular event detection block 1312; the wait block1316 also continues at the ventricular event detection block 1312. Ingeneral, the ventricular event detection block 1312 aims to detect an Rwave or a ventricular contraction. As described above, parasympatheticstimulation may act to increase end diastolic volume and indirectly toincrease passive contractility via the Frank-Starling mechanism;however, parasympathetic stimulation is potentially detrimental toactive contractility. Thus, according to the method 1300, it isdesirable to avoid parasympathetic stimulation at a time in the cardiaccycle that may impair active contractility.

Upon detection of a particular event, the method 1300 then initiatesparasympathetic stimulation in an initiation block 1320. The stimulationmay continue for a set period of time, may continue until detection ofanother cardiac event or may continue for a certain amount of time basedon detection of a subsequent cardiac event. As shown in FIG. 13, themethod 1300 includes an atrial event detection block 1324. For example,such a detection block may detect an atrial paced event and/or anintrinsic atrial event. Upon detection of the atrial event, the method1300 proceeds to set a timer to a fraction of an atrio-ventricularinterval in a set timer block 1328. Upon expiration of the timer, a haltparasympathetic stimulation block 1332 halts parasympatheticstimulation. In this example, parasympathetic stimulation is halted toensure that the parasympathetic stimulation does not cause anysignificant detriment to active contractility. Thereafter, the exemplarymethod 1300 continues at the decision block 1308, at the detection block1312 or at another suitable point (e.g., a decision block that decideswhether further parasympathetic stimulation is required). Of course, asmentioned above, parasympathetic stimulation may be delivered during arefractory period of the myocardium (e.g., the myocardium proximate toone or more electrodes). Hence, the exemplary method 1300 optionallyincludes stimulating during a refractory period, for example, to reducethe risk of producing an evoked response from the myocardium.

Selecting and/or Positioning Leads and/or Electrodes

An exemplary method for selecting and/or positioning a lead and/or anelectrode is optionally implemented during implantation and/or afterimplantation. For example, during an implantation procedure, a patientis optionally instrumented to monitor heart function. For example, heartrate may be monitored via an EKG and contractility via arterial pressuresensors (e.g., the time derivative of the pressure can provide a goodmeasure of contractility). In this example, monitoring of cardiacfunction and/or other functions may occur through use of externalinstrumentation and/or through use of implanted leads and/or sensors.

Consider a situation wherein parasympathetic tuning via parasympatheticnerve stimulation aims to decrease heart rate, to increase end diastolicvolume and/or to decrease AV conduction. In such a situation, anexemplary method includes adjusting pulse amplitude and/or pulsefrequency to relatively high values, automatically or manually (e.g., animplantable device having a lead and/or electrode implantation,selection and/or positioning mode(s)). In this exemplary method, throughuse of stimulation pulses and monitoring of cardiac function and/orother functions, a lead and/or electrode is positioned duringimplantation to achieve an optimal and/or a satisfactory decrease inheart rate (e.g., an increase of therapeutic value), increase in enddiastolic volume and/or decrease in AV conduction. In this exemplarymethod, for example, a physician may slowly move a lead throughout anappropriate region and deliver pulses until a desired decrease in heartrate, increase in end diastolic volume and/or decrease in AV conductionis seen maximally via monitoring.

In yet another exemplary method, a lead and/or an electrode areoptionally positioned to decrease sympathetic activity while at the sametime minimizing stimulation effects on heart rate. Once a “sweet spot”is found, then pulse parameters are optionally adjusted to minimizeelectrical power consumption, for example, by previously mentionedexemplary methods.

Conjunct to Sympathetic Blockade

Pharmacological approaches to blockade of the sympathetic system includeinhibition of central sympathetic outflow (using central sympatholytics,e.g. rilmenidine, moxonidine), blockade of the catecholaminebiosynthetic pathway (dopamine beta hydroxylase antagonists) andblockade of the cardiac effects of sympathetic activation(beta-adrenoceptor blocking agents), see, e.g., Krum, “Sympatheticactivation and the role of beta-blockers in chronic heart failure”,Aust. NZ J. Med., 29(3): 418-427 (1999).

Beta-blockers aim to offset deleterious effects associated withsympathetic activity. However, a high beta blocker level may lead tobradycardia, symptomatic hypotension, excessive fatigue, and/orprogressive signs or symptoms of congestive heart failure. Under suchcircumstances, beta blocker dose reduction is typically necessary and/oradministration of an inotropic agent, see, e.g., Shakar and Bristow,“Low-level inotropic stimulation with type III phosphodiesteraseinhibitors in patients with advanced symptomatic chronic heart failurereceiving beta-blocking agents”, Curr. Cardiol. Rep., 3(3): 224-231(2001). However, these methods inherently require human intervention,which may take days or weeks. Consequently, under such circumstances aneed exists to reduce blockade or antisympathetic therapy in a moreexpeditious manner.

Thus, according to various exemplary methods and/or stimulation devicesdescribed herein, parasympathetic stimulation is used in patientssubject to sympathetic blockade therapy. Under such circumstances, forexample, a baseline blockade is provided through administration of anagent while a variable blockade is provided through parasympatheticstimulation. Parasympathetic stimulation includes afferentparasympathetic stimulation (e.g., to decrease release ofnorepinephrine) and/or efferent parasympathetic stimulation. Further,rather than adjusting beta blocker dosage, parasympathetic therapy canbe adjusted. Indeed, use of such methods and/or devices can maintain atleast some benefits of blockade while providing increased heart rateand/or inotropy when needed. In such patients, increased heart rateand/or inotropy are needed, for example, during times of physicalexertion, including, but not limited to, sex. During such times,parasympathetic stimulation is, for example, diminished or halted.

CONCLUSION

Although exemplary methods and/or devices have been described inlanguage specific to structural features and/or methodological acts, itis to be understood that the subject matter defined in the appendedclaims is not necessarily limited to the specific features or actsdescribed. Rather, the specific features and acts are disclosed asexemplary forms of implementing the claimed methods and/or devices.

1. A method comprising: detecting a physiological parameter indicativeof a need for increased cardiac output; and responsive to detecting thephysiological parameter indicative of a need for increased cardiacoutput, stimulating a parasympathetic nerve to increase vagal tone andincrease end diastolic volume, wherein the stimulation of theparasympathetic nerve is initiated during a ventricular refractoryperiod to increase passive ventricular contractility.
 2. The method ofclaim 1, wherein the detecting comprises sensing a pressure.
 3. Themethod of claim 1, wherein the stimulating occurs postinspiration only.4. The method of claim 1, further comprising synchronizing thestimulating to one or more events in a cardiac cycle.
 5. The method ofclaim 1, further comprising halting the stimulation after a set periodof time.
 6. The method of claim 1, further comprising halting thestimulating and implementing a diagnostic algorithm after the halting.7. The method of claim 6, further comprising comparing results of thediagnostic algorithm after the halting of stimulation to resultsacquired prior to the halting of stimulation.
 8. An apparatuscomprising: means for detecting a physiological parameter indicative ofa need for increased cardiac output; means for detecting contractions ofone or more chambers of a patient's heart; and means for stimulating aparasympathetic nerve, responsive to the detecting, to increase vagaltone and to increase end diastolic volume, wherein the stimulation isinitiated during a ventricular refractory period to increase passiveventricular contractility.
 9. The apparatus of claim 8, wherein themeans for detecting comprises one or more sensors.
 10. The apparatus ofclaim 8, wherein the means for stimulating a parasympathetic nervecomprises an electrode positionable proximate to the parasympatheticnerve.